β-lactam derivatives of the cephem sulphone type

Abstract

PCT No. PCT/EP90/02189 Sec. 371 Date Jun. 12, 1992 Sec. 102(e) Date Jun. 12, 1992 PCT Filed Dec. 14, 1990 PCT Pub. No. WO91/09036 PCT Pub. Date Jun. 27, 1991.Cephalosporins of the formula (I): <IMAGE> (I) wherein m is one or two; n is zero, one or two; A and B are organic residues; and R1 and R2 are halogen or hydrogen atoms or organic groups are endowed with elastase inhibitory activity. Two processes for their preparation starting from the corresponding 4-acyl cephem are also provided.

We claim: 
     
       1. A compound of the formula (I') ##STR68## wherein n is zero, one or two; m is one or two; A is methyl or C 2  -C 10  straight or branched alkyl, alkenyl, alkynyl; C 3  -C 8  cycloalkyl; dimethylphenyl, diphenylmethyl; phenyl or benzyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl and benzyl groups are either unsubstituted or substituted by fluoro, chloro, carboxy, C 1  -C 4  alkoxycarbonyl, carbamoyl, carbamoyloxy, methylsulphonyl, diazo, hydroxy, methoxy, ethoxy, tertbutoxy, benzyloxy, acetoxy, pivaloyloxy, benzoxy or phenylacetoxy;   B is (1') optionally substituted C 1  -C 5  straight or branched alkyl or alkenyl or C 1  -C 5  cycloalkyl;   (2') optionally substituted phenyl;   (3') optionally substituted aralkyl; or   (4') an optionally substituted 5- or 6-membered saturated or unsaturated heterocyclic ring, containing one or more heteroatoms selected from O, S, N, optionally fused to a second said 5- or 6-membered carbocyclic or heterocyclic ring, the substituents for the groups defined under (1')-(4') being selected from hydroxy, C 1  -C 3  alkoxy, phenoxy, benzyloxy, benzhydryloxy, methylthio, carboxy, carboxymethyl, carboxyethyl, carbamoylmethyl, amino, acetamido, formamido, dimethylamino, diethylamino, dimethylaminoethyl, nitro, cyano, sulpho, sulphamoyl, tetrazolyl, formimidoyl, ureido, chloro, fluoro, bromo, oxo, C 1  -C 5  alkyl, vinyl and allyl;     R 1  is hydrogen or (1') chloro, fluoro or bromo;   (2') C 1  -C 4  alkyl, 1-(hydroxyl)ethyl, 1-(benzyloxy)-ethyl, 1-(benzyloxycarbonyloxy)ethyl, 1-(phenylacetoxy)ethyl, isopropyl phenyl, benzyl or allyl;   (3') methoxy, ethoxy, isopropoxy, phenoxy or benzyloxy;   (4') methylthio;   (5') formyloxy, acetoxy or phenylacetoxy;   (6') mesyloxy or tosyloxy;   (7') formamido, acetamido, fluoroacetamido, trifluoroacetamido or chloroacetamido;   (8') R v  -Ala-NH, wherein R v  is either acetyl, tert-butoxycarbonyl, benzoxycarbonyl or HOOC--CH 2  CH 2  C(O)--;   (9') R v  -Val-NH wherein R v  is as defined above;   (10') Val-Pro-NH, Lys-NH or Ala-Ala-Pro-NH, wherein the terminal amino group of Val, Lys or Ala respectively or the α-amino group of Lys is either free or acylated with a group R v  as defined above;     R 2  is either hydrogen or (1') methyl, chloromethyl, bromomethyl, benzyl, ethyl, propyl or phenyl;   (2') chloro;   (3') methoxy or benzyloxy;   (4') methylthio;   (5') formyl, acetyl, benzoyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl;   (6') methoxymethyl, ethoxymethyl, isopropoxymethyl, benzyloxymethyl, phenoxymethyl or 3-pyridyloxy-methyl, wherein the phenyl and pyridyl rings are either unsubstituted or substituted by one group or two groups which are the same or different, the said group or groups being chosen from hydroxy, carboxy, amino and C 1  -C 4  alkoxy-carbonyl;   (7') methylthiomethyl, phenylthiomethyl, methylsulphonylmethyl, phenylsulphynylmethyl or phenylsulphonylmethyl;   (8') --CH 2  --S-Het wherein Het is a heterocyclic ring, preferably chosen from ##STR69## (9') acetoxymethyl, benzoxymethyl, phenylacetoxymethyl or C 3  -C 6  alkanoyloxymethyl, each of which is either unsubstituted or substituted by one or more groups selected from carboxy, hydroxy and C 1  -C 3  alkoxy;   (10') trialkylammoniomethyl, wherein the alkyl group is chosen from methyl, ethyl, propyl, N-methylpyrrolidiniomethyl, N-methylpiperidiniomethyl and N-methylmorpholiniomethyl;   (11') pyridiniomethyl which is either unsubstituted or substituted on the heterocyclic ring by fluoro, chloro, methoxy, hydroxy, carboxy or carbamoyl; or a pharmaceutically or veterinarily acceptable salt thereof.     
     
     
       2. A compound according to claim 1 of the formula (I') in which n is zero, one or two; m is one or two; A is selected from hydrogen, methyl, ethyl, tert-butyl, neo-pentyl, benzyl, 1-phenylethyl, dimethylphenyl, diphenylmethyl, propenyl, phenylethenyl, cyclopentyl, 1-carboxycyclopentyl, diazomethyl, chloromethyl, hydroxymethyl, methoxymethyl, acetoxymethyl and pivaloyloxymethyl;   B is (1") methyl, ethyl, propyl, isopropyl, allyl, carboxymethyl, 2-carboxy-2-aminoethyl, cyclopropyl, cyclopentyl, ethoxycarbonylmethyl, 2-carboxyethyl, 2-sulphoethyl or 1,2-dicarboxyethyl;   (2") phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-carbamoylphenyl, 4-aminophenyl, 4-acetamidophenyl, 2-acetamidophenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 4-benzyhydryloxycarbonylphenyl, 4-tert-butoxycarbonylphenyl, 3-carboxy-4-nitrophenyl, pentafluorophenyl, 4-carboxymethylphenyl or 4-sulphophenyl;   (3") benzyl, p-carboxybenzyl, p-tert-butoxycarbonylbenzyl, m-carboxybenzyl, o-carboxybenzyl, p-benzhydryloxycarbonylbenzyl or p-sulphobenzyl;   (4") an heterocyclic ring chosen from: ##STR70##  wherein R VI  is hydrogen, methyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 3-benzhydryloxycarbonylpropyl, 2-dimethylaminoethyl, 2-sulphoethyl, ethyl, propyl, phenyl or benzyl; ##STR71##  wherein X is oxygen, sulphur or NR VII , R VII  being hydrogen, methyl, phenyl or carboxymethyl; ##STR72##  wherein R VIII  is hydrogen, methyl, benzyl or benzhydryl; and ##STR73## R 1  is hydrogen, chloro, bromo, fluoro, methoxy, formamido, acetamido, trifluoroacetamido, methyl, ethyl, propyl, isopropyl, allyl, 1-(hydroxy)ethyl, 1-benzyloxycarbonyloxy)ethyl, 1-(benzoyloxy)ethyl, 1-(phenylacetoxy)ethyl, ethoxy, propoxy, isopropoxy;     R 2  is hydrogen, methyl, ethyl, bromomethyl, hydroxymethyl, methoxymethyl, carbamoyloxymethyl, carboxy, phenoxymethyl, phenyl, acetoxymethyl, aminomethyl, pyridiniomethyl, benzyloxy-methyl, 3-pyridyloxymethyl, carboxymethoxymethyl, N-carboxy-methylcarbamoyloxymethyl, carboxymethylcarbonyloxymethyl, p-carboxybenzoyloxymethyl, glycyloxymethyl or a CH 2  -S-Het group wherein Het is a heterocyclic ring chosen from ##STR74## or a pharmaceutically or veterinarily acceptable salt thereof.   
     
     
       3. A pharmaceutical or veterinary composition comprising a suitable carrier and/or diluent and, as an active principle, a compound according to claim 1 or 2, or a pharmaceutically or veterinarily acceptable salt thereof. 
     
     
       4. A method of treating a mammal suffering from an inflammatory or degenerative disease caused by a proteolytic enzyme, which method comprises administering thereto a therapeutically effective amount of a compound of formula (I') as defined in claim 1 or 2, or a pharmaceutically or veterinarily acceptable salt thereof. 
     
     
       5. A method according to claim 4, wherein the disease is selected from the group consisting of emphysema, adult respiratory distress syndrome, rheumatic fever, spondylitis, gout, lupus and psoriasis.